Kent Mouw: Yeah, thanks so much for having me. It's a pleasure to be here and excited to talk about some of our recent work. So, just a little bit of background. As Dr. Ballas mentioned, I'm a radiation oncologist. My primary clinical responsibility is seeing and taking care of bladder cancer patients. And so, we typically at my institution meet these bladder cancer patients in a multidisciplinary setting, and then move forward with recommendations for what we feel like is the best treatment strategy for each patient. As a radiation oncologist, I'm particularly interested in trimodal therapy. A couple of years ago, we as a group decided that we wanted to begin collecting plasma circulating tumor DNA data for our MIBC patients. And so, to do that, we began ordering it when we were meeting these patients upfront, and then throughout their treatment course, and then during surveillance following treatment. As many of you are probably aware, there's pretty good data showing that ctDNA status in the plasma is prognostic for outcomes in patients with MIBC receiving cystectomy-based care. And so, on the left I'm showing a couple of the landmark studies.
The top is from Aarhus, the bottom is from Mount Sinai, each demonstrating this really strong association between detectability of ctDNA in the plasma, and outcomes following cystectomy. Similarly, in the post-cystectomy space, ctDNA has also been demonstrated to be both prognostic and now, in fact, predictive. These are data from IMvigor010 and 011, which was published more recently, demonstrating that in the post-cystectomy setting, ctDNA status predicts benefit from adjuvant immunotherapy. And so, really powerful biomarker in the cystectomy space for patients with MIBC. As a radiation oncologist particularly interested in trimodal therapy, I was motivated to try to understand the dynamics between ctDNA detectability in the blood, and outcomes in patients receiving trimodal therapy. And so, to that end, we accrued a cohort of patients, and most of our patients were treated like this. So, this is the classic TMT paradigm. Patients undergo a maximal safe transurethral resection of their bladder tumor, and then receive definitive-intent concurrent chemoradiation, and then enter surveillance that includes exam, cross-sectional imaging, and cystoscopy. These are the characteristics of our cohort. So, these are patients who were treated with bladder-directed radiation at Brigham and Women's Hospital, Dana-Farber Cancer Center, as well as at MGH Cancer Center. We pooled our experiences across Boston. This cohort consisted of 84 patients, and you can see on the right in the table that these are relatively representative of what a common TMT population looks like. So these patients, the median age was 75, the majority were male.
Most were clinical T2, the majority were node-negative, although there were a minority of patients who were either node-positive or primary non-urothelial histology. A subset of our patients did receive neoadjuvant chemotherapy, which is part of the TMT paradigm in certain patients. And you can see below there the median dose that was used. These patients almost exclusively were treated with either 55 Gray in 20 fractions, or 64 Gray in 32 fractions, which are both standard curative-intent doses. The patients underwent plasma ctDNA testing with this commercially available Signatera assay, and then we correlated those ctDNA data with clinical outcomes. And so, maybe starting from the left here. So, at diagnosis, following transurethral resection, and prior to chemoradiation, about a third of our patients had detectable ctDNA in their plasma. There was a correlation between the likelihood of detectability of the ctDNA at diagnosis and clinical stage. Maybe not surprisingly, you can see that patients with more advanced disease, clinical T3 or 4 disease, or clinically node-positive disease, were more likely to have detectable ctDNA prior to chemoradiation, than patients with T2N0 disease. And then what was of particular interest to us was tracking the dynamics of ctDNA detectability through chemoradiation. I try to show that here on the right in the Sankey diagram. You can see that for the majority of patients who had detectable ctDNA prior to chemoradiation, the majority of them, 11 out of 15, actually converted to having undetectable ctDNA at that first initial post-chemoradiation assessment time point. There was a small subset of patients, four out of the 15, that had persistently detectable ctDNA, and as I'll show you on the next slides, the outcomes in those patients were unfortunately quite poor.
The majority of the patients with undetectable ctDNA prior to chemoradiation maintained that undetectable status through chemoradiation, with just two patients converting from negative to positive through chemoradiation. And here I think really the Kaplan-Meier curves that tell the tale. And so, the left set of curves are based on the ctDNA status immediately prior to chemoradiation. You can see there's a strong correlation between ctDNA detectability and metastasis-free survival in the post-CRT setting. However, even more strong was the association of that first post-chemoradiation therapy time point that's shown in the right set of curves. You can see this really strong correlation with, unfortunately, all patients who had detectable ctDNA at that first post-chemoradiation assessment, developing metastatic disease typically within the first year or so of completing chemoradiation. Because TMT is bladder-preserving therapy, we were also interested in the ctDNA dynamics in patients who had a local recurrence of their disease. And so, we know that a subset of patients treated with TMT will have either a muscle-invasive or a non-muscle-invasive recurrence. Here you can see there were 12 such patients in our cohort of about 85 patients. What was really interesting to us, is that unlike patients who recurred with metastatic disease, nearly all of whom had a ctDNA test that was positive preceding the clinical diagnosis of metastatic disease, none of these patients with a local-only recurrence, whether it be muscle-invasive or non-muscle-invasive, had a ctDNA test that was positive prior to the diagnosis of that local-only recurrence.
And so, really suggesting that this assay is a very sensitive marker of early metastatic disease, but is less sensitive when it comes to these local recurrences that happen in the bladder. I hope that this data really adds to the body of literature we have around using plasma ctDNA testing in this context, and I think provides some color around its use specifically in the bladder preservation TMT setting.
Leslie Ballas: Thank you, Dr. Mouw. This is really exciting work and something that we've all been kind of waiting to really see and understand a little bit. Can you just tell me quickly, the first post-TMT assessment of ctDNA, what was the median timeframe from TMT?
Kent Mouw: Yeah, that's a great question. Because this was a clinical cohort outside of a trial, there was some variability. Our routine practice is to do cystoscopies and imaging typically in that, say, six to 12 week post-chemoradiation time point. And so, the vast majority of patients had their first post-chemoradiation therapy assessment at some point during that timeframe, what I think is a pretty common first post-treatment assessment time point. That said, again, because this wasn't on a trial, there were some patients whose first post-TMT assessment fell outside of that timeframe. But that was, I would think, the most common.
Leslie Ballas: At your institution, are your medical oncologists starting adjuvant chemotherapy, or some adjuvant therapy, based on ctDNA positivity following TMT without radiographic or cystoscopic findings?
Kent Mouw: Yeah, that's really interesting. I think the short answer is no, because this is early data. We need to demonstrate in a clinical trial that ctDNA can be predictive of benefit from therapy in the post-TMT setting. But I think that naturally we all maybe carry a bit more worry and maybe err on the side of the short end of the next cycle, in terms of when we want to scan these folks. Because I think seeing a ctDNA that remains detectable after TMT, at least in our cohort, albeit relatively small, was a really poor prognostic sign. And so, I think we worry a lot about those patients, and try to keep as close an eye on them as we can.
Leslie Ballas: The last graph that you showed is something that I find to be the most interesting, is that the ctDNA in the post-TMT setting does not correlate with local recurrence. And so, I guess my question is, what do you think of these ctDNA-positive patients prior to TMT? Is that ctDNA coming from micrometastatic disease, and perhaps the chemotherapy that we always thought was just radio-sensitizing is actually affecting that ctDNA positivity, since it doesn't seem to be a correlate to local disease?
Kent Mouw: Yeah, I think it's a really interesting question. I mean, we don't quite have the data to really address it directly. Certainly, that's a possibility that the chemotherapy is maybe having more systemic effect than we thought it might in the "radio-sensitizing" context. Another possibility is that at the time of diagnosis and initial TURBT, many of these patients have tumors that are relatively large. We know that tumor size, in some studies, correlates with likelihood of having detectable ctDNA in the plasma. Thankfully, if done properly, the post-TMT surveillance is done frequently enough such that just the volume of disease present when patients do have a recurrence is probably a lot smaller in the post-TMT setting than it is at diagnosis. And so, I think we all believe some local tumors probably are capable and do shed ctDNA into the blood. If that's correlated with size, then one possible, at least partial explanation, is that patients often have a lot more tumor bulk at diagnosis in that initial TURBT, than they do if they suffer a local recurrence in the post-TMT setting. There's certainly other interesting speculative possibilities as well, but that's one thing I think that feels like could be part of it.
Leslie Ballas: 19% of your patients had neoadjuvant chemotherapy. Did you look specifically at that population to see if those patients all cleared their ctDNA?
Kent Mouw: Yeah, that's a really interesting question. We did take a look. The challenge was that the numbers just get kind of small, because not every patient, for instance, of the 19% who got neoadjuvant chemotherapy, not all of them had ctDNA assessments, pre-neoadjuvant chemo, post-neoadjuvant chemo pre-chemoradiation, and then again post-chemoradiation. Anecdotally, it did feel like most of the patients, for the handful of patients for whom we had that set of data, most of them cleared their ctDNA with the neoadjuvant chemotherapy. That feels reassuring, in the context of then moving forward with the chemoradiation. Again, it's a subset of patients who don't clear their ctDNA through a therapy, whether that be neoadjuvant chemo or through chemoradiation, and this is maybe obvious, but it's that population of patients who seem like they do the worst.
Leslie Ballas: Similarly, and I know it again is very small numbers, but did you look at radiation fields at all, in terms of whether someone had a small pelvis versus bladder only, and if there was some signal that maybe that contributed to clearance of ctDNA?
Kent Mouw: Yeah, it's interesting. Unfortunately, given the size of the cohort and the relative heterogeneity, we didn't look specifically at that. I would say that the majority of node-negative patients didn't have an elective pelvic nodal field treated, but there were, say, 15% of patients who were clinically node-positive in our cohort, and in which case we were treating nodes typically. And so, yeah, I think it's easy, interesting to speculate, and maybe even more so, and this is completely speculative, whether radiating the pelvis and radiating the lymphatics around the bladder may subsequently impact the likelihood that a tumor in the pelvis is physically capable of putting its tumor DNA into the bloodstream, because you've irradiated those lymphatics. That's complete speculation. We don't know that to be the case. But it's interesting to wonder whether that's another contribution of the dynamics of plasma-based ctDNA testing in the post-TMT setting.
Leslie Ballas: Thank you, Dr. Mouw, for sharing your data, talking with us today. It's clear that this is an area of exciting research and that there's a lot yet to be done. I know that there's going to be analysis of the SWOG/NRG 1806 population, in which there is blood plasma collected, and so we'll look forward to certainly that larger cohort randomized patient population data. But thank you so much for joining me.
Kent Mouw: Yeah. Thanks again for the invite. It was great to talk.